MRx JANUARY 2020 CLINICAL ALERT YOUR MONTHLY SOURCE FOR DRUG INFORMATION HIGHLIGHTS

FDA UPDATES ON DRUG nitrites plus ranitidine or nizatidine in IMPURITIES the body and the formation of NDMA. EDITORIAL Currently, the FDA is instructing patients The United States (US) Food and who are taking these medications to STAFF Drug Administration (FDA) continues limit intake of foods containing nitrites, to investigate the presence of such as processed meats and those nitrosamine impurities in various containing the preservative sodium EDITOR IN CHIEF medications. Outside the US, low levels nitrite. An alternative is to switch to a Maryam Tabatabai of N-nitrosodimethylamine (NDMA), medication that has not been found PharmD similar to amounts observed in certain to contain NDMA, such as another H2 foods and water, have recently been blocker (e.g., cimetidine or famotidine) found in the diabetes medication or a proton pump inhibitor (PPI). EXECUTIVE EDITOR metformin. As a result, some metformin Carole Kerzic products have been recalled in other RPh 2020 COPD GUIDELINES countries. To date, no US metformin products have been recalled. The The 2020 Global Initiative for Chronic DEPUTY EDITORS US FDA is assessing metformin to Obstructive Lung Disease (GOLD) Stephanie Christofferson determine whether any samples strategy for prevention, diagnosis, and PharmD contain NDMA, and if so, whether these management of chronic obstructive levels are greater than the previously pulmonary disease (COPD) has been Jessica Czechowski defined acceptable daily intake level of released. Overall guiding principles are PharmD 96 ng/day or 0.32 ppm. If high levels unchanged from the 2019 update. The are detected, the agency will inform changes for 2020 include: (1) additional Lara Frick the public and initiate product recalls. details on the use of eosinophils as PharmD, BCPS, BCPP The FDA recommends that patients an efficacy biomarker for inhaled with type 2 diabetes mellitus (T2DM) corticosteroids (ICS), (2) further Leslie Pittman who are managed with metformin delineation of the role of non-drug PharmD continue therapy and that healthcare therapies, and (3) refinement of the professionals (HCP) continue to prescribe diagnosis of exacerbation with additional Anna Schreck Bird metformin as indicated. Metformin is details on other potential diagnoses. PharmD recommended as the preferred initial medication for T2DM management. Key revisions include the addition of a new table around use of non-pharmacological In addition, the FDA announced they are treatments for COPD. Non-drug requesting manufacturers of the oral therapies include patient education histamine-2 (H2) blockers ranitidine on self-management and the role of and nizatidine to test all product lots pulmonary rehabilitation, influenza and for NDMA. The FDA is requiring that pneumococcal vaccinations, nutritional manufacturers inform the agency if supplementation, physical activity, thresholds exceed the acceptable daily and management of risks (smoking, intake limit and withhold releasing environmental exposures). A second affected lots. The FDA will also assess table was added with several differential the link between the presence of diagnoses to consider before diagnosing

Download| JANUARY at: 2019 magellanrx.com a COPD exacerbation; these include lung conditions, adalimumab plus MTX. ICER determined that the evidence such as embolism, pneumonia, and edema, as well as provides moderate certainty that, when combined with MTX, cardiac arrhythmias. The addition of a new infographic upadacitinib offers a better net health benefit compared outlines key factors to consider when starting ICS therapy to adalimumab. Two head-to-head trials comparing in combination with 1 or 2 long-acting bronchodilators. tofacitinib to adalimumab found no significant differences There is strong support for starting an ICS in patients with in clinical outcomes between the 2 agents; therefore, a history of hospitalizations for COPD exacerbations or ≥ ICER concluded with high certainty that tofacitinib and 2 moderate exacerbations per year, despite long-acting adalimumab provide comparable net health benefit. bronchodilator maintenance therapy; blood eosinophils There are no head-to-head data to compare baricitinib > 300 cell/µL; and a history of or concurrent asthma. to adalimumab. Short-term (within 6 months) safety ICS initiation can be considered in patients with blood profiles of JAK inhibitors, adalimumab, and cDMARDs eosinophils of 100 to 300 cells/μL and 1 moderate were comparable, and long-term (≥ 1 year) safety profiles COPD exacerbation per year. For patients with repeated were similar among the JAK inhibitors. pneumonia events, blood eosinophils < 100 cell/µL, or a history of mycobacterial infection, initiating ICS therapy is not recommended. Finally, the infographic on the COPD BEHAVIORAL HEALTH CORNER management cycle was expanded to include diagnosis, initial assessment, and initial management of COPD, as FDA FRAMEWORK FOR GUIDANCE OF well as review of patient’s clinical status and adjustment ACUTE OPIOID PRESCRIBING of therapy (pharmacologic and non-pharmacologic). The FDA commissioned the National Academies Other notable revisions to the guidelines include the of Sciences, Engineering, and Medicine (NASEM) addition of the anti-interleukin (IL)-5 agents benralizumab to create a framework in which to evaluate opioid and mepolizumab as options with anti-inflammatory prescribing for acute pain and to identify areas for potential. In addition, recent data suggest that antibiotic further research. While appropriate access to opioids usage can be restricted without negative health outcomes is crucial, the FDA encourages “right size” prescribing when the C-reactive protein (CRP) is low. and a reduction in the number of people who are needlessly exposed to opioids. Based on their findings, the panel recommends that evidenced-based clinical ICER REPORT ON JAK INHIBITORS practice guidelines (CPG) use an accepted method The Institute for Clinical and Economic Review (ICER) for grading the evidence and rating the strength of published an evidence report on the effectiveness and recommendations. CPGs should clearly specify use economic value of oral Janus kinase (JAK) inhibitors in in specific areas, such as patient population and adults with moderate to severe rheumatoid arthritis subpopulations, treatment setting, and prior treatment. (RA). Evidence from studies comparing JAK inhibitors The NASEM recommends that clinical trial data be to conventional disease modifying antirheumatic drugs specific to drug, dosage, and duration, and urges the (cDMARDs), such as methotrexate (MTX), revealed significant use of morphine milligram equivalents (MME) when improvements in disease measures for both upadacitinib comparing efficacy of opioid agents. Stakeholders, such and tofacitinib. ICER concluded with high certainty that as professional societies, healthcare organizations, upadacitinib and tofacitinib provide substantial net health and insurers, should assess CPG impact on short- benefit compared to cDMARDs; however, evidence is and long-term opioid prescribing practices. These insufficient to compare baricitinib to the cDMARDs. Based include health outcomes, opioid misuse, and opioid- on economic modeling, ICER found that upadacitinib related overdoses and deaths. The panel prioritizes provides marginal clinical benefit compared to adalimumab certain medical and surgical conditions that should but at a higher cost. Nevertheless, cost-effectiveness be considered in CPGs for acute pain management. estimates for upadacitinib fall under the cost-utility Researchers and developers of CPGs should outline threshold of $150,000 per quality-adjusted life year. appropriate use and optimal prescribing strategies, including opioid and nonpharmacologic alternatives, In the SELECT-COMPARE study, upadacitinib plus MTX and assess their impact on opioid use in the setting was associated with a significant, though modest, of acute pain. Lastly, the panel recommends further increase in rates of disease remission, American College research in key areas, such as population-based patient of Rheumatology (ACR) response, change in pain, and outcomes, impact of clinical setting on prescribing, improvement in Health Assessment Questionnaire for and association of intermediate markers (e.g., unused Rheumatoid Arthritis Disability Index (HAQ-DI) compared to medication, long-term opioid use) on health outcomes.

2 | JANUARY 2020 DRUG INFORMATION HIGHLIGHTS • Flu Season Update (2019-2020): The Centers for Disease • Lannett is voluntarily recalling 2 lots of levetiracetam Control and Prevention (CDC) reported that the influenza oral solution 100 mg/mL to the consumer level due to like illnesses (ILI) activity in the US continued to rise contamination with Bacillus subtilis. While there is potential during the week ending December 28, 2019. Nationwide, for severe infection if used in immunocompromised the influenza B/Victoria virus predominates, followed patients, no adverse events have been reported related by A(H1N1)pdm09. The District of Columbia, New to affected lots of the anti-epileptic drug. York City, Puerto Rico, and 34 states reported high ILI • The FDA reported that Jazz Pharmaceuticals will activity; 9 states reported moderate activity; and the discontinue distribution of the atypical antipsychotic remaining states reported low to minimal activity. At clozapine orally disintegrating tablet (ODT) (Fazaclo®) last report, 6.9% of patient visits were due to ILI, which based on a commercial decision. Generic clozapine is above the national baseline of 2.4%; although, lower ODT remains commercially available. routine healthcare visits during this holiday week may have skewed this number. No shortages of influenza • The International Consensus Group released new antivirals to treat or prevent the flu have been reported. recommendations regarding the management of nonvariceal upper gastrointestinal bleeding (UGIB), • Since 2001, the proportion of individuals with human as an update of their 2010 guidance. Although the immunodeficiency virus (HIV) resistant to certain annual incidence of acute UGIB has declined, the 30-day drugs has grown from 11% to 29%. The FDA recently mortality rate is 11%. The recommendations address approved a next generation sequencing (NGS) test, the the endoscopic management as well as pharmacological ® Sentosa SQ HIV Genotyping Assay, for the detection management and secondary prophylaxis. Regarding of HIV type-1 drug resistance mutations from patient’s pharmacological management, high risk patients with blood. This approval marks the first HIV drug resistance bleeding ulcers with successful endoscopic treatment testing assay utilizing this NGS technology. The test shoud receive high-dose PPI therapy with an intravenous can be used to identify virus mutations before or (IV) loading dose, followed by a continuous infusion during antiviral treatment. The assay can detect 342 for 3 days. It is suggested that an oral PPI then be HIV drug-resistant mutations and is intended for use given twice daily for 14 days, followed by once daily to help guide antiretroviral therapy. treatment, for a total duration dependent on the • Glenmark issued a consumer-level voluntary recall of severity of the bleeding lesion. In terms of secondary all unexpired lots of ranitidine 150 mg and 300 mg prophylaxis, PPI therapy is suggested for patients with tablets due to the presence of NDMA above acceptable previous ulcer bleeding who are receiving antiplatelet limits. The company will stop distribution of ranitidine or anticoagulant therapy. products as it continues to investigate causes.

PIPELINE NEWS: UPCOMING PRESCRIPTION DRUG/BIOSIMILAR USER FEE ACT (PDUFA/BsUFA) DATES

• January 2020: pembrolizumab (Keytruda®); IV • January 20, 2020: semaglutide (Rybelsus®); oral GLP-1 programmed cell death 1 (PD-1) inhibitor; bladder cancer agonist; CV risk reduction in patients with T2DM; Novo (monotherapy, BCG-unresponsive, high-risk, non-muscle Nordisk. invasive); Merck. • January 23, 2020: tazemetostat; oral EZH2 inhibitor; • January 2020: AR101; oral peanut protein; peanut allergy; Sarcoma; Royalty. Aimmune. • January 24, 2020: fidaxomicin (Dificid®); oral macrolide • Jan-Mar 2020: empagliflozin/linagliptin/metformin antibiotic; Clostridium difficile-associated diarrhea extended-release (ER); oral fixed-dose sodium- (pediatrics); Merck. glucose co-transporter 2 (SGLT2) inhibitor/dipeptidyl • January 28, 2020: risperidone ER; intramuscular (IM) peptidase-4 (DPP-4) inhibitor/biguanide; T2DM; atypical antipsychotic; schizophrenia, bipolar disorder; Boehringer-Ingelheim. Luye. • Jan-Mar 2020: osilodrostat; oral aldosterone synthase • January 29, 2020: leuprolide mesylate depot (ready- inhibitor; Cushing’s syndrome; Recordati/Novartis. to-use): SC gonadotropin-releasing hormone agonist; • January 20, 2020: semaglutide (Ozempic®); SC glucagon- prostate cancer; Foresee. like peptide-1 (GLP-1) receptor agonist; cardiovascular (CV) risk reduction in patients with T2DM; Novo Nordisk.

3 | JANUARY 2020 RECENT FDA APPROVALS DRUG NAME DESCRIPTION MANUFACTURER New Drugs givosiran • NDA approval 11/20/2019; Breakthrough Therapy, Orphan Drug, Priority Review (GivlaariTM) • Indicated for acute hepatic porphyria Alnylam • Aminolevulinate synthase 1 (ALAS1)-directed small interfering ribonucleic acid (siRNA) • Injection: 189 mg/mL single-dose vial (SDV) • Recommended dosage is 2.5 mg/kg administered SC once monthly by an HCP • Available medical support is recommended to manage anaphylactic reaction cenobamate • NDA approval 11/21/2019 (Xcopri®) • Indicated for the treatment of partial-onset seizures in adults

SK Life Science • Voltage-gated sodium current inhibitor/GABAA ion channel modulator • Tablets: 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg • Recommended initial dosage is 12.5 mg orally once daily, titrated up to 200 mg once daily; maximum daily dose is 400 mg • Product availability is expected in 2Q2020, following controlled substance scheduling riluzole • 505(b)(2) NDA approval 11/22/2019; Orphan Drug (ExservanTM) • Indicated for the treatment of amyotrophic lateral sclerosis (ALS) Aquestive • Benzothiazole Therapeutics • Oral film: 50 mg • Recommended dosage is 50 mg orally twice daily, at least 1 hour before or 2 hours after a meal; should be taken without water • Aquestive Therapeutics is seeking a US commercial partner voxelotor • NDA approval 11/25/2019; Accelerated Approval, Breakthrough Therapy, Orphan Drug, (OxbrytaTM) Priority Review, Rare Pediatric Disease Global Blood • Indicated for the treatment of sickle cell disease (SCD) in adults and pediatrics ages ≥ 12 Therapeutics years; continued approval may depend on confirmatory trials • Hemoglobin S polymerization inhibitor • Tablet: 500 mg • Recommended dosage is 1,500 mg orally once daily without regard to food • Available through the manufacturer’s specialty pharmacy partner network methotrexate • 505(b)(2) NDA approval 11/27/2019 (ReditrexTM) • Indicated for: Cumberland » the management of severe, active RA and polyarticular juvenile idiopathic arthritis (pJIA) in patients who are intolerant of or inadequately responsive to first-line therapy; » symptomatic control of severe, recalcitrant, disabling psoriasis (PSO) in adults who are inadequately responsive to other therapies • Folate analog metabolic inhibitor • Injection: 7.5 mg/0.3 mL, 10 mg/0.4 mL, 12.5 mg/0.5 mL, 15 mg/0.6 mL, 17.5 mg/0.7 mL, 20 mg/0.8 mL, 22.5 mg/0.9 mL, and 25 mg/mL strengths in single-dose, pre-filled syringes • Recommended initial dosage is listed below; adjust dose to achieve optimal response » RA: 7.5 mg SC once weekly » pJIA: 10 mg/m2 SC once weekly » PSO: 10 mg to 25 mg SC once weekly • Patient or caregiver may administer with proper training on administration and handling • Boxed warnings for severe toxic reactions, including embryo-fetal toxicity and death ANDA = Abbreviated New Drug Application; BLA = Biologics License Application; NDA = New Drug Application; Q = Quarter; sBLA = Supplemental Biologics License Application; sNDA = Supplemental New Drug Application; 505(b)(2) = FDA approval pathway that allows for submission of data from studies not conducted by or for the applicant.

4 | JANUARY 2020 RECENT FDA APPROVALS continued DRUG NAME DESCRIPTION MANUFACTURER New Drugs continued infliximab-axxq • BLA approval 12/06/2019; biosimilar to Remicade® (AvsolaTM) • Indicated for the management of adults with active ankylosing spondylitis (AS), active Amgen psoriatic arthritis (PsA), or chronic severe PSO, and adult and pediatric patients with moderately to severely active RA, Crohn’s disease (CD), or ulcerative colitis (UC) • Tumor necrosis factor (TNF) inhibitor • Injection: 100 mg lyophilized powder in a SDV • Recommended dosages are given IV over at least 2 hours » PSO, PsA, and UC: 5 mg/kg at weeks 0, 2, and 6, then every 8 weeks thereafter » CD: 5 mg/kg at weeks 0, 2, and 6, then every 8 weeks thereafter; may increase up to 10 mg/kg in adults » RA: 3 mg/kg at weeks 0, 2, and 6, then every 8 weeks thereafter; may increase up to 10 mg/kg every 4 weeks » AS: 5 mg/kg at weeks 0, 2, and 6, then every 6 weeks thereafter • Boxed warning for serious infections and malignancy golodirsen • NDA approval 12/12/2019; Accelerated Approval, Orphan Drug, Priority Review (Vyondys 53™) • Indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have Sarepta a confirmed mutation of the DMD gene that is amenable to exon 53 skipping; continued approval may depend on results of confirmatory trials • Antisense oligonucleotide • Injection: 100 mg/2 mL SDV • Recommended dosage is 30 mg/kg administered once weekly IV over 35 to 60 minutes enfortumab • BLA approval 12/18/2019 vedotin-ejfv • Indicated for the treatment of adult patients with locally advanced or metastatic urothelial (Padcev™) cancer who have previously received a PD-1 or programmed death-ligand 1 (PD-L1) inhibitor, Astellas and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting • Nectin-4-directed antibody and microtubule inhibitor conjugate • Injection: lyophylized powder in 20 mg and 30 mg SDVs • Recommended dosage is 1.25 mg/kg (not to exceed 125 mg) administered by an HCP IV over 30 minutes on days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity tazarotene • 505(b)(2) NDA approval 12/18/2019 (Arazlo™) • Indicated for the topical treatment of acne vulgaris in patients ages ≥ 9 years Bausch Health • Retinoid • Lotion: 0.045% • Apply a thin layer to affected areas once daily • Product availability is expected in the first half of 2020 ebola zaire • BLA approval 12/19/2019; Breakthrough Therapy, Priority Review vaccine, live • Indicated for the prevention of disease caused by Zaire ebolavirus in individuals ages ≥18 (Ervebo®) years; does not protect against other species of Ebolavirus or Marburgvirus; duration of Merck protection is unknown • Injection: 1 mL suspension in a SDV • Recommended dosage is a single 1 mL IM injection • Product availability is expected in 3Q2020 ANDA = Abbreviated New Drug Application; BLA = Biologics License Application; NDA = New Drug Application; Q = Quarter; sBLA = Supplemental Biologics License Application; sNDA = Supplemental New Drug Application; 505(b)(2) = FDA approval pathway that allows for submission of data from studies not conducted by or for the applicant.

5 | JANUARY 2020 RECENT FDA APPROVALS continued DRUG NAME DESCRIPTION MANUFACTURER New Drugs continued levamlodipine • 505(b)(2) NDA approval 12/19/2019 maletate • Indicated as monotherapy or in combination with other antihypertensive agents for the (Conjupri®) treatment of hypertension, to lower blood pressure CSPC Ouyi • Calcium channel blocker • Tablets: 1.25 mg, 2.5 mg, and 5 mg • Recommended initial dosage in adults is 2.5 mg once daily with a maximum dose of 5 mg once daily; initial dosage in small, fragile, or elderly adults is 1.25 mg once daily; initial dosage in pediatrics is 1.25 mg to 2.5 mg once daily (dosages > 2.5 mg in pediatrics have not been studied) fam-trastuzumab • BLA approval 12/20/2019; Accelerated Approval, Breakthrough Therapy deruxtecan-nxki • Indicated for the treatment of adults with unresectable or metastatic HER2-positive breast (Enhertu®) cancer who have received ≥ 2 prior anti-HER2-based regimens in the metastatic setting; Daiichi Sankyo/ continued approval may depend on confirmatory trial results AstraZeneca • HER2-directed antibody and topoisomerase inhibitor conjugate • Injection: 100 mg lyophilized powder in a SDV • Recommended dosage is 5.4 mg/kg given as IV infusion once every 21 days until disease progression or unacceptable toxicity; administer initial dose over 90 minutes, if tolerated give subsequent doses over 30 minutes • Do not substitute for or with trastuzumab (Herceptin®) or ado-trastuzumab (Kadcyla®) • Boxed warnings for interstitial lung disease and embryo-fetal toxicity lembroxant • NDA approval 12/20/2019 (Dayvigo™) • Indicated for the treatment of adult patients with insomnia, characterized by difficulties Eisai with sleep onset and/or sleep maintenance • Orexin receptor antagonist • Tablets: 5 mg and 10 mg • Recommended dosage is 5 mg orally taken no more than once per night, immediately before going to bed, with at least 7 hours remaining before the planned time of awakening; maximum dosage is 10 mg once daily; administration with or soon after a meal may delay sleep onset • Product availability will follow Drug Enforcement Administration (DEA) scheduling, which is expected to occur within 90 days of FDA approval ubrogepant • NDA approval 12/23/2019 (Ubrelvy™) • Indicated for the acute treatment of migraine with or without aura in adults Allergan • Calcitonin gene-related peptide receptor antagonist • Tablets: 50 mg and 100 mg • Recommended dosage is 50 mg or 100 mg orally as needed; may administer a second dose at least 2 hours after the initial dose; do not exceed 200 mg in a 24-hour period • Product availability is expected in 1Q2020 lumateperone • NDA approval 12/23/2019 (Caplyta®) • Indicated for the treatment of schizophrenia in adults Intra-Cellular • Atypical antipsychotic Therapies • Capsule: 42 mg • Recommended dosage is 42 mg once daily with food; no dose titration is required • Boxed warning for increased mortality in elderly patients with dementia-related psychosis • Product availability is expected in late 1Q2020 ANDA = Abbreviated New Drug Application; BLA = Biologics License Application; NDA = New Drug Application; Q = Quarter; sBLA = Supplemental Biologics License Application; sNDA = Supplemental New Drug Application; 505(b)(2) = FDA approval pathway that allows for submission of data from studies not conducted by or for the applicant.

6 | JANUARY 2020 RECENT FDA APPROVALS continued DRUG NAME DESCRIPTION MANUFACTURER Expanded Indications acalabrutinib • sNDA approval 11/21/2019 (Calquence®) • New indication for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic AstraZeneca lymphoma (SLL) • Recommended dosing is 100 mg orally every 12 hours insulin glargine • sNDA approval 11/26/2019 (Toujeo®) • Expanded indication to include pediatrics 6 to 17 years old with diabetes mellitus (types Sanofi 1 and 2) • Recommended SC dosage is individualized based on type of diabetes, metabolic needs, blood glucose monitoring results, and glycemic control goal atezolizumab • sBLA approval 12/03/2019 (Tecentriq®) • New indication for first-line treatment of adults with metastatic non-squamous non-small Genentech cell lung cancer with no EGFR or ALK genomic tumor aberrations, in combination with paclitaxel protein-bound and carboplatin • Recommended dosage is 1,200 mg IV every 3 weeks until disease progression or unacceptable toxicity tofacitinib ER • sNDA 12/12/2019 (Xeljanz® XR) • New indication for the treatment of adults with moderately to severely active UC who have Pfizer had an inadequate response or who are intolerant to TNF blockers; tofacitinib immediate- release (Xeljanz®) was approved for this indication in May 2018 • Recommended induction dosage is 22 mg orally once daily for 8 to 16 weeks; maintenance dosage is 11 mg once daily icosapent ethyl • sNDA 12/13/2019 (Vascepa®) • New indication as adjunct to maximally tolerated statin therapy to reduce the risk of Amarin myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adults with elevated triglycerides (≥ 150 mg/dL) and established cardiovascular disease (CVD) or diabetes mellitus and ≥ 2 additional CVD risk factors • Recommended dosage is 2 g twice daily taken orally with food enzalutamide • sNDA 12/16/2019 (Xtandi®) • New indication for the treatment of metastatic castration-sensitive prostate cancer; Astellas previously approved for castration-resistant prostate cancer • Recommended dosage is 160 mg (four 40 mg capsules) orally once daily

ANDA = Abbreviated New Drug Application; BLA = Biologics License Application; NDA = New Drug Application; Q = Quarter; sBLA = Supplemental Biologics License Application; sNDA = Supplemental New Drug Application; 505(b)(2) = FDA approval pathway that allows for submission of data from studies not conducted by or for the applicant.

References: annals.org cdc.gov fda.gov goldcopd.org icer-review.org

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